Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women

Arterioscler Thromb Vasc Biol. 2003 Jun 1;23(6):1116-21. doi: 10.1161/01.ATV.0000074146.36646.C8. Epub 2003 May 1.


Objective: The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin.

Methods and results: In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E2) 50 microg (tE2 group, n=33), oral E2 1 mg (oE2 group, n=37), or oral E2 1 mg combined with gestodene 25 microg (oE2+G group, n=33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE2, +26.9%; oE2, +102.7%; oE2+G, +69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE2, -4.1%; oE2, -7.9%; oE2+G, -5.8%), free protein S (tE2, -7.1%; oE2, -8.4%; oE2+G, -5.2%), and protein C in the oE2+G group (-6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr.

Conclusions: Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activated Protein C Resistance / chemically induced*
  • Administration, Cutaneous
  • Administration, Oral
  • Aged
  • Biomarkers
  • C-Reactive Protein / analysis
  • Double-Blind Method
  • Estradiol / administration & dosage*
  • Estradiol / adverse effects
  • Estradiol / pharmacology
  • Estrogen Replacement Therapy*
  • Female
  • Hemostasis / drug effects*
  • Humans
  • Middle Aged
  • Norpregnenes / administration & dosage
  • Norpregnenes / adverse effects
  • Norpregnenes / pharmacology*
  • Postmenopause / blood*
  • Protein C / analysis*
  • Protein S / analysis
  • Prothrombin / analysis
  • Risk Factors
  • Venous Thrombosis / blood*
  • Venous Thrombosis / chemically induced


  • Biomarkers
  • Norpregnenes
  • Protein C
  • Protein S
  • Gestodene
  • Estradiol
  • Prothrombin
  • C-Reactive Protein